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National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Food and Nutrition Board; Committee to Review the Dietary Reference Intakes for Sodium and Potassium; Oria M, Harrison M, Stallings VA, editors. Dietary Reference Intakes for Sodium and Potassium. Washington (DC): National Academies Press (US); 2019 Mar 5.

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Dietary Reference Intakes for Sodium and Potassium.

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8Sodium: Dietary Reference Intakes for Adequacy

Sodium is a physiologically essential nutrient. Accordingly, the Dietary Reference Intakes (DRIs) for adequacy serve as an important reference value with a variety of applications. The extent to which an indicator of sodium adequacy has been identified and characterized in the apparently healthy population is at the crux of the committee's decision regarding which DRI for adequacy to establish and at what levels. For an Estimated Average Requirement (EAR) to be established, evidence of a causal relationship between intake of the nutrient and the indicator of adequacy, as well as evidence of an intake–response relationship, is needed to determine the distribution of requirement for adequacy in the population. As described in Chapter 1, once an EAR is determined, a Recommended Dietary Allowance (RDA) can be established. When there is insufficient evidence to establish an EAR and an RDA, a DRI for adequacy is still indispensable, as it provides a benchmark for dietary planning and assessment; in such cases, an Adequate Intake (AI) is established using other data-driven approaches and indicators.

Guided by the DRI organizing framework (see Chapter 1, Box 1-2) and the considerations under the expanded DRI model (see Chapter 2), this chapter describes the committee's review of indicators to inform the sodium DRIs for adequacy and presents its approach and determination of updated reference values for the DRI age, sex, and life-stage groups. The committee's decision was informed by its evaluation of evidence on sodium intake requirements in apparently healthy individuals, as well as its review of the evidence on adverse effects associated with continuing low sodium intakes. In addition to the indicators considered, the chapter includes conclusions from the Agency for Healthcare Research and Quality systematic review, Sodium and Potassium Intake: Effects on Chronic Disease Outcomes and Risks (AHRQ Systematic Review) (Newberry et al., 2018), where relevant, and additional evidence from the committee's supplemental literature searches and information-gathering activities. This chapter presents the committee's rationale and conclusions regarding the suitability of these indicators to inform the sodium DRI for adequacy. For context, the committee's findings are preceded by a brief summary of the approach taken to establish the sodium AIs in the Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate (2005 DRI Report).

SODIUM ADEQUATE INTAKE LEVELS ESTABLISHED IN THE 2005 DRI REPORT

Collecting data to construct intake–response relationships for estimating sodium EARs is not feasible within the context of the current food supply because of the challenges in consuming extremely low levels of sodium. In 2005, an EAR and an RDA were not established for sodium because of inadequate intake–response evidence; instead, AIs were established with an approach that was different from that of other essential nutrients. The sodium AIs for adults 19–50 years of age were “based on meeting sodium needs of apparently healthy individuals, as well as that of other important nutrients using foods found in a Western-type diet,” with the assumption that the individual was moderately active in a temperate climate (IOM, 2005, p. 308). As supporting evidence, the AI was noted as exceeding sodium intake levels that had been associated with adverse effects on blood lipid concentrations and insulin resistance. Serum and plasma sodium concentrations, plasma renin activity, and blood pressure were explored as potential indicators but were not used to establish the sodium AIs. For children 1–18 years of age and older adults (51 years of age and older), AIs were extrapolated from the AI set for adults 19–50 years of age based on reported energy intake.

REVIEW OF POTENTIAL INDICATORS OF SODIUM ADEQUACY

The original intent of setting adequacy reference intake values for nutrients was to prevent deficiency diseases in the population; therefore, adequacy levels have been established based on such deficiency symptoms. However, health concerns in the United States and Canada have shifted toward the high prevalence of chronic diseases. Consequently, the idea of introducing chronic diseases as indicators to establishing reference values characterizing adequate intakes, either EARs and RDAs or AIs, has been implemented by various DRI committees. In contrast, the current committee faces an expanded DRI model, in which the relationship between nutrient intake and chronic disease can be characterized in a separate DRI category, termed herein the Chronic Disease Risk Reduction Intake (CDRR). This committee interpreted the guidance provided in the Guiding Principles for Developing Dietary Reference Intakes Based on Chronic Disease (Guiding Principles Report) as differentiating considerations of adequacy and chronic disease. Pursuant to the first step of the DRI organizing framework (see Chapter 1, Box 1-2), the committee's review of the evidence to establish the sodium DRIs for adequacy focuses on identifying indicators of sodium adequacy. Despite this conceptual delineation, the committee recognized the importance of reviewing evidence of potential harmful health effects of low sodium intakes in establishing the sodium DRIs for adequacy. In this context, the evidence on the relationship between sodium intake and chronic disease was reviewed to ensure that the selected sodium adequacy DRI values did not potentially lead to detrimental effects. The committee considered this use as being different from using such evidence as an indicator to establish a sodium CDRR.

To explore which indicators could potentially be used to inform the sodium DRIs for adequacy, the committee first considered aspects of sodium physiology, including adaptations of blood sodium concentration to various conditions and hyponatremia. Hyponatremia is defined as a serum sodium concentration of less than 135 mmol/L, with severe hyponatremia being below 120 mmol/L (Sterns, 2015); the concentration of blood sodium at which symptoms of sodium deficiency (e.g., nausea, poor balance, decreased ability to think, headaches, confusion, seizures, or coma) appear are not well characterized. The human body tightly regulates water and sodium balance; however, in instances where these two homeostatic goals are at odds with one another, water and fluid balance are prioritized. As such, in most instances hypo- or hypernatremia are driven by disturbances in fluid balance, and its hormonal control, rather than by disturbances in sodium balance or by sodium intake (Andreoli, 2000). To that end, blood sodium concentration is not a reliable indicator of usual dietary sodium intake or status because most often it reflects inadequate or excessive intakes or losses of water from the body, increased vasopressin release, or occasionally drug effects (e.g., thiazide diuretics, synthetic vasopressin, nonsteroidal anti-inflammatory drugs, antidepressants).

From its information-gathering activities and scoping literature searches (see Appendix D), the committee was unable to identify a sensitive or specific biomarker of sodium status that could be used to determine the distribution of sodium requirements in the apparently healthy population. In the absence of such an indicator of sodium adequacy, the committee reviewed the evidence from balance studies and considered the context of potential harms of low sodium intake.

Balance Studies

Balance studies measuring total intake and losses have been used in the past to assess adequacy based on the concept that neutral balance reflects homeostasis for the nutrient in adults. Such a neutral balance can be, and has been for some nutrients, interpreted as meeting the physiological requirement and, thus, informative to specify an adequate intake level (NASEM, 2018). For example, the EAR for calcium in adults was specified on the basis of calcium balance (IOM, 2011). Applying this rationale to sodium would mean that for an adult to be in neutral balance, intake would be equal to the sum of all sodium losses (sweat, urine, fecal, and other). Individuals with intakes less than losses would be considered in negative balance, indicating deficient intakes. Individuals with intakes greater than losses would be considered in positive balance. In states of growth, positive balance might be necessary to support tissue accretion and, thus, be adequate; in adults, positive balance might indicate intakes above those meeting physiological requirements. To have confidence in such balance studies, intake of sodium and losses by all routes need to be rigorously determined for a sufficient duration in controlled feeding studies to ensure that homeostasis has been achieved. In addition, rigorous balance studies will minimize confounding factors, such as bioavailability and adaptation, that could affect the interpretation of balance.

Evidence Presented in the 2005 DRI Report

The 2005 DRI Report provided an overview of topics related to sodium balance and considered the effects of heat and physical activity on sodium losses. Urinary sodium excretion was characterized as being approximately equal to sodium intake for individuals in a steady state of sodium and fluid balance. Excretion of sodium in feces was described as minimal, although it was noted that increases in sodium intake led to increases in fecal sodium excretion (Allsopp et al., 1998). Sodium losses in sweat were described as being widely variable and dependent on factors such as sweat rate, sodium intake, and heat acclimation. In the 2005 DRI Report it was concluded that “free-living individuals can achieve sodium balance following acclimation under a variety of conditions, including low sodium intake and extreme heat” (IOM, 2005, p. 277).

Evidence from the Committee's Supplemental Literature Searches

As the committee reviewed the evidence from the limited balance studies available, the expected challenge of measuring total sodium losses from the body was evident (see Table 8-1). Only two studies measured all sodium losses from total urine, feces, and whole body sweat (Alsopp et al., 1998; Palacios et al., 2004), and only one of these rigorously measured dietary sodium intake (Palacios et al., 2004). Palacios et al. (2004) examined sodium retention in black and white adolescent females consuming a low- (1,300 mg/d [57 mmol/d]) or high-sodium (4,000 mg/d [172 mmol/d]) diet in a randomized, crossover design. Although all losses were assessed, the study did not control for environmental parameters, such as humidity or temperature, and urinary sodium excretion showed high intra-individual variability. In addition to incomplete sodium loss measurements, a number of studies did not directly measure total sodium intake, but relied on food composition tables or manufacturers' labeled sodium content (Heer et al., 2000, 2009; Lerchl et al., 2015). Such failure to measure all sodium losses or reliance on food composition estimates of intake introduces uncertainty and imprecision in total sodium intake that limit the interpretation of balance.

TABLE 8-1. Sodium Balance Studies Summarized by Completeness of Assessment of Intake and Losses.

TABLE 8-1

Sodium Balance Studies Summarized by Completeness of Assessment of Intake and Losses.

The committee noted new challenges that have been identified based on the emerging data since 2005. First, one study reports high intra-individual variability in sodium losses on controlled intake of sodium and an infradian rhythm (i.e., lasting longer than 1 day) (Lerchl et al., 2015), which would require longer duration for a balance study to ensure that homeostasis is achieved and to enable appropriate consideration of the high intra-individual variability. The study suggested that at least 7 days of urinary sodium assessment are needed to achieve classification accuracy greater than 90 percent (Lerchl et al., 2015). Most balance studies, however, have been conducted only for 3 to 8 days. One exception is a study by Kirkendall et al. (1976) that was conducted for 4 weeks on each sodium intake level; this longer-duration study fed controlled intakes from liquid formula diet, which may be less relevant to food-based diets. Furthermore, high intra-individual variability may mean that randomized crossover (which will need longer periods to achieve equilibrium) or sequential study designs are essential for sodium balance studies and that parallel randomized designs are less appropriate for sodium balance studies. Second, evidence is emerging on sequestration of sodium in the skin concomitantly with water and muscle without concomitant water (Kopp et al., 2013; Xu et al., 2015). Sequestration may be influenced by age (Kopp et al., 2013), hypertensive status (Kopp et al., 2013), inflammation (Xu et al., 2015), and other factors. Thus, unmeasured sequestration might confound the interpretation of balance in these studies. The relationship of sequestration of sodium in skin or muscle to sodium intake is an important, but unexamined, concern relative to balance studies. Such confounding limits the interpretation in that negative balance might represent the loss of sodium from sequestration as opposed to actual deficiency and positive balance might represent sequestration to maintain a level of sodium in these sites.

Committee's Synthesis of the Evidence

Current balance studies have limitations and do not offer sufficient data for characterizing the distribution of sodium requirements in the apparently healthy population. Limitations of existing studies include uncertainties of the duration needed to allow for equilibration in light of high intra-individual variability and the potential confounding by sequestration of sodium in skin and muscle. As discussed in Chapter 12, evidence is needed from studies in which sodium intake is controlled and chemically determined in rigorous feeding studies of sufficient duration to encompass infradian rhythm and intra-individual variability. Such ideal studies would measure all losses of sodium including at a minimum urinary, whole body sweat, and fecal losses.

The better-designed balance studies summarized in Table 8-1 may be informative if considered in combination with other approaches for assessing adequacy. Despite the limitations of the balance studies, negative balance was reported with sodium intakes of 230–2,210 mg/d (10–96 mmol/d) across the eight studies conducted in adults. By comparison positive balance was reported with intakes as low as 1,525 mg/d (66 mmol/d; at 25°C [77°F]). Only one study reported an approximately neutral balance of intake and excretion (sodium balance reported as +4.6 ± 117.3 mg/d), and only for one sodium intake level (1,525 mg/d [66 mmol/d]) with daily heat stress (40°C [104°F] for 10 hours) (Allsopp et al., 1998). Only one study in adolescent females rigorously measured sodium intake and all sodium losses and reported positive balance with intakes of 1,300–4,000 mg/d (57–172 mmol/d).

ADDITIONAL EVIDENCE CONSIDERED: POTENTIAL HARMFUL HEALTH EFFECTS OF LOW SODIUM INTAKES

The committee's review of the evidence did not identify other potential indicators of sodium adequacy or deficiency that could be used to estimate sodium requirements in the apparently healthy population. However, data from observational studies have suggested an increase in risk of specific chronic diseases at low intake levels of sodium. Therefore, to minimize the potential for harmful health effects beyond deficiency at levels of intake around sodium adequacy, the committee considered the evidence related to the potential for such levels to increase biomarkers of chronic diseases (insulin resistance, blood pressure, and lipid concentrations), cardiovascular disease outcomes, and all-cause mortality. This section describes the committee's assessment of such evidence and its appropriateness and limitations for its use as support of the sodium DRIs for adequacy. The committee based its assessment using evidence from the AHRQ Systematic Review and evidence from its supplemental literature searches. This section also summarizes findings from another systematic review for comparison (Eeuwijk et al., 2013).

Type 2 Diabetes, Glycemic Control, and Insulin Sensitivity

Evidence Presented in the 2005 DRI Report

The 2005 DRI Report concluded that the effects of sodium reduction on insulin resistance were sparse and inconsistent. However, the potential adverse effects on insulin resistance at low sodium levels (700 mg/d [30 mmol/d]) were noted as a consideration for the selection of a sodium AI in the 2005 DRI Report.

Evidence from the Committee's Supplemental Literature Search

A systematic review assessed evidence of relationships between low levels of sodium intake (230–1,953 mg/d [10–85 mmol/d] for 5–28 days, after a period of normal-to-high sodium intake of 4,596–6,894 mg/d [200–300 mmol/d]) and a variety of measures, including insulin resistance (Eeuwijk et al., 2013). Among the eight trials included in the systematic review studying insulin sensitivity, only three reported a lower insulin sensitivity with sodium reduction in the ranges listed above. The systematic review concluded such levels of sodium restriction may decrease insulin sensitivity, although results were inconsistent (Eeuwijk et al., 2013).

The committee reviewed the evidence from randomized clinical trials and prospective cohort studies published since 2003 on the relationship between sodium intake and blood glucose, insulin, and incident type 2 diabetes (for literature search details, see Appendix E). The committee identified two randomized controlled trials reviewing the effect of dietary sodium on insulin sensitivity and glucose tolerance (Meland and Aamland, 2009; Suckling et al., 2016) and one prospective cohort study examining the relationship between sodium intake and type 2 diabetes (Hu et al., 2005). The identified randomized clinical trials did not find differences in measures of glucose control or insulin production between groups on low and high sodium intakes. The prospective cohort study reported that high sodium intake was associated with higher risk of incident type 2 diabetes.

Committee's Synthesis of the Evidence

There is insufficient evidence to suggest that there is potential harm in lower sodium intakes with respect to incident type 2 diabetes, and measures of glucose and insulin status.

Blood Pressure

Evidence Presented in the 2005 DRI Report

The 2005 DRI Report noted that some investigators have found blood pressure increases as a result of reducing sodium intake levels. The apparent rise in blood pressure in some individuals was described as potentially being a pressor response, potentially caused by an overactive renin-angiotensin-aldosterone system (RAAS), intrinsic variability in blood pressure, or imprecise blood pressure measurements. The 2005 DRI Report concluded that, given these considerations, the apparent rise in blood pressure with reductions in sodium intake could not be used as an indicator of sodium adequacy.

Evidence Provided in the AHRQ Systematic Review

The AHRQ Systematic Review included one observational cohort study in Taiwanese adult men and women with evidence of an increase in hypertension risk with lower sodium intakes. Compared with individuals in the second quartile of sodium intake (median of 2,367 mg/d [103 mmol/d]), those in the first quartile (median of 1,448 mg/d [63 mmol/d]) had a suggestive, but nonsignificant, increased risk of hypertension (relative risk = 1.24; p = .07) (Chien et al., 2008). Sodium was assessed through estimated 24-hour urinary sodium from a single overnight urine sample.1 The AHRQ Systematic Review rated this study as having a high risk of bias. The AHRQ Systematic Review made no conclusion on whether lowering sodium intake could increase blood pressure.

Committee's Synthesis of the Evidence

Based on the committee's assessment of the trials that explored blood pressure as an outcome, there is moderate strength of evidence that the positive linear relationship between sodium intake and blood pressure extends downward to as low as 850–1,800 mg/d (37–78 mmol/d) (see Chapter 10). There is also insufficient evidence that low sodium intakes are associated with increased blood pressure.

Plasma Lipid Concentrations

Evidence Presented in the 2005 DRI Report

The 2005 DRI Report described two systematic reviews that explored the relationship between reduced sodium intake and plasma lipid concentrations and that provided contrasting results (Graudal et al., 1998; He and MacGregor, 2002). One of the systematic reviews included trials with extreme reductions of sodium (Graudal et al., 1998), whereas the other included trials with moderate reductions in sodium (He and MacGregor, 2002). Reductions in sodium from high sodium intakes of 6,434 mg/d (280 mmol/d) to low intakes of 1,287 mg/d (56 mmol/d) resulted in significant increases in total and low-density lipoprotein (LDL) cholesterol concentrations (Graudal et al., 1998). Moderate reductions in sodium (net changes of sodium ranged from 920–2,714 mg/d [40–118 mmol/d]) did not result in such increases (He and MacGregor, 2002). These meta-analyses also differ in that trials of 1 week or less duration were included in Graudal et al. (1998), but not in He and MacGregor (2002). No studies were identified for which plasma lipid concentrations was the primary endpoint. The 2005 DRI Report described the selected sodium AI for adults 19–50 years of age as a level above which some studies had reported increased plasma lipid concentrations.

Evidence Provided in the AHRQ Systematic Review

The AHRQ Systematic Review did not include plasma lipids in its outcomes of interest but recorded them from studies on an ad hoc basis when measured as an adverse event. The AHRQ Systematic Review identified four such publications (from three different trials) showing no significant difference in plasma lipid concentrations (total cholesterol, LDL, high-density lipoprotein [HDL], triglycerides) (Harsha et al., 2004; Meland and Aamland, 2009; Sacks et al., 2001; Sciarrone et al., 1992). Based on a low strength of evidence, the AHRQ Systematic Review concluded that sodium reduction does not appear to significantly affect plasma lipids concentrations.

Evidence from the Committee's Supplemental Literature Search

A systematic review assessed evidence of relationships between low levels of sodium intake (230–1,953 mg/d [10–85 mmol/d] for 5–28 days, after a period of normal-to-high sodium intake of 4,596–6,894 mg/d [200–300 mmol/d]) and a variety of measures including plasma lipids (Eeuwijk et al., 2013). The review concluded that there is (1) inconsistent evidence that sodium restriction significantly increases total cholesterol (from seven randomized controlled trials) or LDL cholesterol (from five randomized controlled trials) and (2) no significant effect on HDL cholesterol (from four randomized controlled trials) or triglyceride (from five randomized controlled trials) concentrations (Eeuwijk et al., 2013).

The committee's supplemental literature searches identified three recent systematic reviews that examined relationships between sodium intake and plasma lipids concentrations (Aburto et al., 2013; Graudal et al., 2017; He et al., 2013). A brief summary of each is provided below and presented in Table 8-2:

TABLE 8-2. Results from Meta-Analyses of Randomized Controlled Trials, Effect of Decreases in Sodium Intake on Blood Lipid Concentrations.

TABLE 8-2

Results from Meta-Analyses of Randomized Controlled Trials, Effect of Decreases in Sodium Intake on Blood Lipid Concentrations.

  • He et al. (2013), which included a Cochrane review and meta-analyses, concluded that there was no significant effect of sodium intake on plasma lipid concentrations based on 8 randomized controlled trials on total cholesterol, 5 randomized controlled trials on LDL cholesterol, 6 randomized controlled trials on HDL cholesterol, and 6 randomized controlled trials on plasma triglyceride concentrations. The major inclusion/exclusion criteria were
    1.

    randomized controlled trials designs;

    2.

    random allocation to modestly reduced salt intake or usual salt intake (control);

    3.

    a minimum intervention period of 4 weeks;

    4.

    exclusion of studies with concomitant interventions; and

    5.

    a reduction in 24-hour urinary sodium within a range of 920–2,760 mg/d (40–120 mmol/d).

  • Aburto et al. (2013) found no significant effect of sodium reduction on plasma lipids concentrations based on 11 randomized controlled trials on total cholesterol, 6 studies on LDL cholesterol, and 9 studies on HDL cholesterol. The major inclusion/exclusion criteria were
    1.

    a minimum intervention period of 4 weeks;

    2.

    sodium intake difference of > 40 mmol/day;

    3.

    randomized controlled trials using 24-hour urinary sodium excretion for assessing sodium intake;

    4.

    inclusion of prospective cohort designs with duration longer than 1 year with any measure of sodium intake, if fewer than three intervention studies included;

    5.

    exclusion of studies with concomitant interventions; and

    6.

    exclusion of studies targeting acutely ill subjects.

  • Graudal et al. (2017) reported significant increases in cholesterol and triglyceride concentrations with reduced sodium based on 26 crossover trials on total cholesterol, 17 crossover trials on LDL cholesterol, 19 crossover trials on HDL cholesterol, and 19 crossover trials on triglyceride concentrations. The major inclusion criteria were
    1.

    randomized controlled trial designs;

    2.

    diets containing any amount of sodium;

    3.

    sodium assessment via 24-hour urinary sodium excretion or estimated from 8-hour excretion;

    4.

    unhealthy patients were excluded; and

    5.

    no exclusion based on the duration of the intervention.

Committee's Synthesis of the Evidence

The absolute effect of sodium intake on blood triglyceride concentrations appears to be small and of questionable biological significance when information about whether individuals had fasted or not is lacking (Stone et al., 2014). In addition, differences in the results of the three identified systematic reviews on the effects of sodium intake on lipid concentrations could result from differences in the inclusion/exclusion criteria such as the duration of the interventions. Although there is ample evidence to include only studies with sodium interventions of 4 weeks or more when blood pressure is the outcome of interest (Law et al., 1991), the limited evidence with serum lipid concentrations suggests that a minimum intervention period is also necessary for serum lipid levels to stabilize. For example, Table 8-2 shows results from different meta-analyses that included studies of various durations. Analyses with the criteria of at least 4 weeks (Aburto et al., 2013; Graudal et al., 2011; He et al., 2013) did not find a significant effect of sodium reduction on total cholesterol, whereas analyses that included studies of shorter duration found a significant mean difference (Graudal et al., 2011, 2017). Given these inconsistencies in the results of the three systematic reviews and the likelihood that study duration is affecting results, there is insufficient evidence about the relationship between a low sodium intake and detrimental effects on blood lipid concentrations.

Cardiovascular Disease Outcomes and All-Cause Mortality

The scientific community has generally supported the idea of a linear positive relationship between higher levels of sodium intake and cardiovascular disease risk, mostly based on studies measuring blood pressure as a biomarker for risk of cardiovascular disease. More recently, however, observational studies have emerged that suggest the possibility that lower intakes of sodium may increase the risk of harmful health outcomes. These studies suggest that the relationship between sodium intake and cardiovascular disease outcomes and mortality is not linear but presents a J or U shape. If confirmed, such a J- or U-shaped relationship might be supportive evidence to specify an AI that minimizes the risk of adverse outcomes at a low level of sodium intake. In contrast to shorter-term studies that evaluated the relationship of sodium intakes and blood pressure, randomized controlled trials of lifestyle interventions that directly measure a chronic disease outcome are less feasible owing to the larger sample size and longer follow-up required. In addition, achieving low intakes of sodium is particularly challenging within current dietary patterns. Hence, most of the evidence evaluating the relationship between lower sodium intake and direct health outcomes derives from observational cohort studies. Although cohort studies are ideal to explore some scientific questions (NASEM, 2017), they are at higher risk of biases, their interpretation requires great care, and their strength of evidence for causality is generally low. In the case of exploring the health effects of lower sodium intake, these methodological issues have fueled controversy. The committee reviewed evidence in the AHRQ Systematic Review to assess whether the J- or U-shaped relationships are caused by methodological limitations or are likely to occur and could be considered as supportive evidence to establish adequacy levels. As background, this section starts with conclusions from other groups who have evaluated this body of evidence.

A 2013 Institute of Medicine (IOM) consensus study report included a comprehensive review of the benefits and adverse effects of reducing sodium intake in the population particularly in the range of 1,500–2,300 mg/d (65–100 mmol/d). Its authors concluded that

evidence from studies on direct health outcomes is inconsistent and insufficient to conclude that lowering sodium intakes below 2,300 mg per day either increases or decreases risk of cardiovascular disease outcomes (including stroke and cardiovascular disease mortality) or all-cause mortality in the general U.S. population. (IOM, 2013, p. 5)

This IOM report also found that the methodological quality of the studies linking lower dietary sodium intake with adverse health outcomes was highly variable and that this variability limited the ability to conduct comparisons. Other reviews have suggested a J-shaped relationship between sodium intake and health outcomes using meta-analyses (Graudal, 2016; Graudal et al., 2014) or qualitative assessments (Alderman and Cohen, 2012) of observational studies. The meta-analyses included studies with diverse methodologies (e.g., food frequency questionnaires, 24-hour urine excretions).

A systematic review of the evidence of associations between low levels of sodium intake and status or adverse health outcomes was conducted for the European Food Safety Authority in preparation for establishing dietary reference values for sodium. The authors reported that low sodium intake may be associated with increased mortality, particularly all-cause mortality and cardiovascular disease mortality (Eeuwijk et al., 2013). This conclusion was based on two (out of three) National Health and Nutrition Examination Survey (NHANES) longitudinal follow-up studies showing an inverse relationship between sodium intake and all-cause mortality (Alderman et al., 1998; Cohen et al., 2006) and on three NHANES studies showing an inverse relationship between sodium intake and cardiovascular disease mortality (Alderman et al., 1998; Cohen et al., 2006, 2008). A major limitation for all three NHANES studies, however, is that estimates of sodium intake come from 24-hour dietary recall data (for limitation of different sodium intake measurement approaches, see Chapter 3).

A comprehensive assessment of cohort studies examining the relationships between sodium intake and health outcomes has provided an in-depth description of methodological issues and their potential contribution to the heterogeneity of the results (Cobb et al., 2014). The authors of the comprehensive assessment applied their criteria to the body of observational studies on sodium and disease outcomes. Based on the potential for both random and systematic error identified in the individual studies, the authors do not recommend the use of this body of evidence to set specific cut points for sodium intake recommendations. Furthermore, the authors concluded that given the multiplicity of different measures of intake and the lack of standardization, comparisons across studies is difficult.

Evidence Provided in the AHRQ Systematic Review

The AHRQ Systematic Review included observational studies that suggested J- or U-shaped relationships between sodium intake and health outcomes. These studies were rated as having high risk of bias based on the AHRQ Systematic Review risk-of-bias tool (see Appendix C, Annex C-1); the committee notes that the high risk of bias ratings closely aligned with the concepts described in Cobb et al. (2014). In addition, the AHRQ Systematic Review did not conduct intake–response meta-regressions with these studies owing to the lack of sufficient data (as specified in their criteria for conducting meta-analysis, three or more studies using 24-hour urinary excretion measures for each outcome). Instead, the AHRQ Systematic Review concluded that “observational studies had limited ability to control for pre-existing health conditions at study baseline that might have resulted in decreased sodium intakes, contributing to potentially spurious associations of lower sodium intakes with morbidity or mortality outcomes of interest” (Newberry et al., 2018, p. 192). Furthermore, the AHRQ Systematic Review notes that “observational studies may have residual confounding, as they could not adjust for all factors that may increase risk for [hypertension], [cardiovascular disease], or [coronary heart disease] outcomes” (Newberry et al., 2018, p. 192). The AHRQ Systematic Review also made the following qualitative conclusions in regard to the relationship between low intakes of sodium and all-cause mortality, cardiovascular disease mortality, combined cardiovascular disease morbidity and mortality, and heart failure:

  • All-cause mortality: The AHRQ Systematic Review concluded that there was insufficient evidence that sodium reduction decreases the risk for all-cause mortality (6 randomized controlled trials in the low intake range of 1,953–3,171 mg/d [85–138 mmol/d]). Out of 13 prospective cohort studies examining associations between sodium intake and all-cause mortality, a U-shaped association was reported in three multicountry studies with overlapping populations that used estimated 24-hour urinary sodium excretion and that were determined to have a high risk of bias (Lamelas et al., 2016; Mente et al., 2016; O'Donnell et al., 2014).
  • Cardiovascular disease mortality and combined cardiovascular disease morbidity and mortality: Based on eight trials, the AHRQ Systematic Review concluded that sodium reduction may significantly decrease the risk for combined cardiovascular disease morbidity and mortality. However, the review also concluded that there is insufficient evidence to draw a conclusion regarding either linear or nonlinear associations between sodium intake levels and cardiovascular disease mortality or associations between sodium intake levels and risks of combined cardiovascular disease morbidity and mortality. Two studies with overlapping populations reported a J or U shape between sodium intake and cardiovascular disease mortality (Lamelas et al., 2016; O'Donnell et al., 2014) and three studies (Lamelas et al., 2016; Mente et al., 2016; O'Donnell et al., 2014) with overlapping populations reported a U-shaped relationship between sodium intake and combined cardiovascular disease morbidity and mortality. All studies were rated as having high risk of bias.
  • Heart failure: The AHRQ Systematic Review reported on two studies that presented evidence on heart failure outcomes. One study reported a U-shaped association (Pfister et al., 2014); the other study reported higher risk of heart failure at higher sodium quartile intake level (He and Macgregor, 2002). Both studies were rated as having high risk of bias.

Committee's Synthesis of the Evidence

The committee notes that the AHRQ Systematic Review did not conduct meta-analyses on the results of observational studies. Pooling results from studies with such varied designs is not appropriate, particularly with different sodium intake assessment methods that carry different systematic and random errors (see Chapter 3 for strengths and weaknesses of the methods); such a pooling might result in spurious changes in size and directionality of the overall effect on the outcome of interest.

The method of sodium intake ascertainment in the observational studies that suggest inverse relationships between sodium intake and chronic diseases is of concern. Six out of seven of the studies that reported higher risk of adverse outcomes at low sodium intake levels in the AHRQ Systematic Review used spot urine sodium measurements converted to estimates of 24-hour urinary sodium excretion by using a formula (e.g., the Kawasaki formula). Two additional studies were published after the release of the AHRQ Systematic Review (Lelli et al., 2018; Mente et al., 2018). Mente et al. (2018) analyzed results from the ongoing Prospective Urban Rural Epidemiology study (for previous results from this study, see also O'Donnell et al., 2014), in which 82,544 individuals in 255 communities were assessed for cardiovascular outcomes during a median of 8.1 years. Morning fasting urine was used to estimate sodium intake using the Kawasaki formula. As with previous results from this ongoing study, a significant inverse association was reported between the lowest tertile of sodium intake (< 4,430 mg/d [< 193 mmol/d]) and cardiovascular disease. The study by Lelli et al. (2018) was conducted in a cohort of two Italian communities enrolled in the 1998–2000 Invecchiare in Chianti—Aging in the Chianti study. An inverse relationship between sodium intake and mortality was reported with higher mortality at sodium intakes below 6,250 mg/d (271 mmol/d). However, the inverse relation was particularly strong in the frail elderly and the group with the lowest sodium intake was older, more sedentary, had more dementia, and could potentially have other medical conditions as well as inadequate calorie intake. Based on the application of the AHRQ Systematic Review risk-of-bias criteria, the committee determined these two observational studies to have a high risk of bias (see Appendix E).

Although spot urine sodium measurements are simpler to obtain than multiple 24-hour urine collections, they introduce important biases that might alter intake–response curves exploring associations of sodium intake with health outcomes (Dougher et al., 2016; Mente et al., 2014). Past methodological studies have partly explained the strengths and limitations of various sodium intake assessment methods and are described in depth in Chapter 3. Some have specifically demonstrated that most sodium exposure measurement methods would result in incorrect levels of intake in individuals, which would lead to misinterpretations regarding associations with health outcomes. For example, Olde Engberink et al. (2017) found that hazard ratios for cardiovascular disease outcomes changed up to 85 percent depending on the sodium intake estimation used (baseline versus 1-year versus 5-year follow-up). A key finding from these validation studies is the systematic bias across the range of sodium intakes, such that spot urine sodium estimates are particularly biased estimates of 24-hour urine sodium at the lower and upper extremes of sodium intake (Dougher et al., 2016; Mente et al., 2014). As the issue at hand is the relationship of low sodium intake with health outcomes, the committee considered the accuracy of spot urine sodium estimates at the low range of intakes as an important concern to this method. Another key piece of evidence for specifically explaining the apparent inverse relationship between sodium intake and mortality derives from recent analyses of data from the Trials of Hypertension Prevention I and II cohort studies (He et al., 2018). The authors compared four different methods of measuring sodium intake: averaged measured,2 average estimated,3 first measured,4 and first estimated.5 The averaged estimated value (a method frequently used in observational studies showing inverse relationships) overestimates sodium intake by about one-third overall. It also tends to overestimate at lower levels and underestimate at higher levels of sodium intake. In addition, whereas the measured value shows a linear relationship between sodium intake and mortality, the estimated value using the Kawasaki formula suggests a J-shaped relationship with mortality. These comparisons are valuable because they show clearly that the sodium exposure assessment can influence the nature of the relationship with endpoints, even when conducted in the same individuals at the same time. Moreover, such comparisons help explain how inaccurate sodium intake measurements could contribute to the apparent higher risk of adverse outcomes at low sodium intake levels observed in some studies.

More broadly, finding an inverse, J- or U-shaped relationship when a direct relationship is expected is not uncommon in the medical literature but it is often largely attributable to reverse causation or confounding. For example, a J- or U-shaped relationship with body mass index (BMI) and mortality has been documented in patients with diabetes, cardiovascular disease, chronic kidney disease, and heart failure. In-depth examination of potential drivers of the J-shaped relationship between BMI and mortality using approaches such as exclusion of those with early deaths or those who were ever smokers attenuated the J-shaped relationship (Tobias et al., 2014). When both ever smokers and those with early deaths were excluded, the expected direct relationship between BMI and all-cause mortality was seen.

Thus, the paradoxical J- and U-shaped relationships of sodium intake and cardiovascular disease and mortality are likely observed because of methodological limitations of the individual observational studies.

DIETARY REFERENCE INTAKES OF SODIUM ADEQUACY

The committee's review of the evidence on potential indicators to inform the sodium DRIs for adequacy revealed the following:

  • There is no sensitive biomarker that can be used to characterize the distribution of sodium requirements in the apparently healthy population.
  • The balance studies have a number of limitations, particularly related to the low number of studies and of subjects in each study, incomplete measurement of intake and losses, unknowns related to sodium sequestration in skin and muscle (storage) in the body, and short equilibration periods in light of emerging evidence of infradian rhythms and high intra-individual variation. These limitations precluded the committee from using such data to estimate median requirements and the distribution of requirements in the apparently healthy population. The balance studies, particularly those with stronger designs, can provide some insight into the levels of sodium intake that may lead to neutral balance.
  • There is a limited and inconsistent body of evidence on the potential harms of low sodium intake. The heterogeneity appears to be caused, in part, by methodological approaches used in observational studies.

The AI is “a recommended average daily nutrient intake level based on observed or experimentally determined approximations or estimates of nutrient intake by a group (or groups) of apparently healthy people who are assumed to be maintaining an adequate nutritional state” (IOM, 2006, p. 11). To establish sodium AIs for adults, which could then be extrapolated to other DRI age, sex, and life-stage groups, the committee drew on its review and synthesis of the evidence for this and the other DRI categories. In particular, as summarized in Chapter 9, randomized controlled trials on sodium included in the AHRQ Systematic Review did not reveal a pattern of reported adverse effects among the low-sodium groups, suggesting that levels of sodium intakes studied did not result in sodium deficiency. Furthermore, the committee established a sodium CDRR for adults 19 years of age and older at 2,300 mg/d (100 mmol/d) (see Chapter 10). In the committee's interpretation of the guidance provided in the Guiding Principles Report, the DRIs for adequacy would be established at or below the sodium CDRR; establishing the sodium AI above the CDRR would be inappropriate, as intakes above 2,300 mg/d (100 mmol/d) are expected to increase risk of cardiovascular disease. To that end, unlike the approach taken for the potassium AI, the committee could not use median population intakes to inform the sodium AIs; median intakes across the DRI age, sex, and life-stage groups in both the United States and Canada exceed the CDRR (see Chapter 11). The committee therefore determined that the sodium AI for adults could be derived from trials with sodium intakes less than 2,300 mg/d (100 mmol/d) and that the strongest designed balance study could provide insight as to whether the selected sodium AI value was appropriate.

The committee concludes that none of the reviewed indicators of sodium requirements offer sufficient evidence to establish Estimated Average Requirement (EAR) and Recommended Dietary Allowance (RDA) values. Adequate Intakes (AIs) are therefore established. Median population intakes are not suitable for establishing the sodium AI because they exceed the sodium Chronic Disease Risk Reduction Intake (CDRR). The committee also concluded that the lowest levels of sodium intake evaluated in randomized trials and evidence from the best-designed balance study conducted among adults were congruent and are appropriate values on which to establish the sodium AIs.

The adult sodium AI value was extrapolated to children and adolescents 1–18 years of age, based on sedentary Estimated Energy Requirements (EERs). For infants 0–12 months of age, sodium intakes of breastfed infants were estimated and were used as the basis of the AI. The sections that follow present additional details on the committee's derivation of the sodium AIs for each of the DRI age, sex, and life-stage groups.

Infants 0–12 Months of Age

Details of the committee's approach to estimating the concentration of sodium in breast milk and the contributions of complementary foods to total sodium intake are provided in Appendix F. To establish the sodium AIs for infants 0–6 and 7–12 months of age, the committee estimated the sodium concentration in mature breast milk. Different concentrations are used for the two infant age groups in the estimates below, as the sodium content of breast milk changes over the course of the first year. To establish the sodium AI for infants 7–12 months of age, sodium intake from complementary foods was estimated and added to the estimated sodium intake from breast milk.

The sodium AI for infants 0–6 months of age is based on estimated sodium intake from breast milk alone. The mean sodium concentration of breast milk for this age group was estimated to be 140 mg/L (6 mmol/L). Assuming an average consumption of 780 mL/day, the sodium AI for infants 0–6 months is established at 110 mg/d (5 mmol/d).

The sodium AI for infants 7–12 months of age is based on estimated sodium intake from breast milk and complementary foods. The mean sodium concentration in breast milk for this age group was estimated to be 110 mg/L (5 mmol/L). Assuming an average breast milk consumption of 600 mL/d, approximately 70 mg/d (3 mmol/d) sodium is consumed from breast milk. Sodium intake from complementary foods was estimated to be 300 mg/d (13 mmol/d). The sodium AI for infants 7–12 months is therefore established at 370 mg/d (16 mmol/d). A summary of the infant sodium AIs is presented in Table 8-3.

TABLE 8-3. Sodium Adequate Intakes, Infants 0–12 Months of Age.

TABLE 8-3

Sodium Adequate Intakes, Infants 0–12 Months of Age.

Children and Adolescents 1–18 Years of Age

For children and adolescents 1–18 years of age, the sodium AIs were derived by extrapolating from the sodium AI for adults (1,500 mg/d [65 mmol/d]; see below). To extrapolate, the committee used rounded average EERs for sedentary children for each age group (see Table 8-4), as compared to an EER for adults of 2,000 kcal/d. EERs were used instead of self- or proxy-reported energy intake owing to potential biases in reported dietary intake data. Extrapolated sodium AIs were mathematically rounded to the nearest 100 mg/d increment. Table 8-5 summarizes the sodium AIs for children and adolescents 1–18 years of age.

TABLE 8-4. Estimated Energy Requirements for Sedentary Children and Adolescents 1–18 Years of Age, by Age Group.

TABLE 8-4

Estimated Energy Requirements for Sedentary Children and Adolescents 1–18 Years of Age, by Age Group.

TABLE 8-5. Sodium Adequate Intakes, Children and Adolescents 1–18 Years of Age.

TABLE 8-5

Sodium Adequate Intakes, Children and Adolescents 1–18 Years of Age.

Adults 19 Years of Age and Older

There was insufficient evidence to establish sodium EARs and RDAs for adults. Therefore, the following evidence informed the committee's judgment in establishing the sodium AI for adults:

  • Lowest sodium intakes from DASH-Sodium and other sodium trials: The Dietary Approaches to Stop Hypertension (DASH)-Sodium trial was a randomized feeding trial in which 412 individuals were assigned to one of two diet arms, a DASH diet (a balanced eating plan) and control diet (a Western-style diet); within each assignment, participants consumed low-, intermediate-, and high-sodium-density foods in random order for 30 days each (Sacks et al., 2001). The range of sodium intakes during the low-sodium period of the DASH-Sodium trial was 985–2,452 mg/d (43–107 mmol/d; average: 1,495 mg/d [65 mmol/d]) among those in the DASH diet arm and 949–2,326 mg/d (41–101 mmol/d; average: 1,449 mg/d [63 mmol/d]) among those in the control diet arm (Murtaugh et al., 2018; Sacks et al., 2001). No deficiency symptoms were reported in this tightly controlled feeding study. In addition, the AHRQ Systematic Review included eight other randomized controlled trials in which sodium intake was reduced to below 1,800 mg/d (see Table 8-6). No deficiency symptoms were reported among the participants in these trials, and there was no pattern of adverse effects (see Chapter 9, Table 9-1).
  • Balance studies: All balance studies had design limitations. In addition, only one study identified a sodium intake level that resulted in an approximately neutral balance at sodium intake of 1,525 mg/d (66 mmol/d) with daily heat stress (40°C [104°F] for 10 hours per day for 5 days). In contrast, this same intake in the same participants without heat stress resulted in positive balance (Allsopp et al., 1998). The committee determined that, among those assessed, the balance study by Allsopp et al. (1998) had the best study design for assessing adults, in that losses from sweat, feces, and urine were accounted for; in addition, this study demonstrated both approximately neutral and positive balance at 1,525 mg/d (66 mmol/d) of intake, dependent on temperature. Negative balance was reported with intakes of sodium from 230–2,210 mg/d whereas positive balance was reported with intakes as low as 1,525 mg/d (66 mmol/d; at 25°C [77°F]) (see Table 8-1).
  • Consideration of potential harmful health effects: There is insufficient evidence that low sodium intakes are associated with potential harmful health effects. The paradoxical J- and U-shaped relationships of sodium intake and cardiovascular disease and mortality are likely observed because of methodological limitations of the individual observational studies, particularly their sodium intake assessment methods.
TABLE 8-6. Trials That Studied the Effects of Sodium Intake Reduction to Low-Range Sodium Levels (850–1,800 mg/d).

TABLE 8-6

Trials That Studied the Effects of Sodium Intake Reduction to Low-Range Sodium Levels (850–1,800 mg/d).

Based on the lowest level of sodium intakes studied in the DASH-Sodium feeding trial and other sodium reduction trials and on the best-designed balanced study, a sodium AI of 1,500 mg/d (65 mmol/d) is appropriate for adults at normal ambient temperatures and not engaged in high-intensity physical activity. For individuals at high ambient temperature and/or performing high-intensity physical activity, a higher sodium intake level than the AI may be needed, but such a level could not be estimated at this time. Several of the randomized controlled trials included in the AHRQ Systematic Review reported allowing participants older than 70 years of age to be included in the study (Appel et al., 2001; Cappuccio et al., 2006; Howe et al., 1994; Hwang et al., 2014; Meland and Aamland, 2009; Nakano et al., 2016; Nestel et al., 1993; Schorr et al., 1996; Wing et al., 1998), but none were exclusively conducted in individuals in that age group. In addition, none of the best-designed balance studies included individuals in this age range. Based on this limited information, there are insufficient data to establish a sodium AI for individuals > 70 years of age that is different from the younger adult population. Based on the evidence presented above, all adults 19 years of age and older have a sodium AI of 1,500 mg/d (65 mmol/d) (see Table 8-7).

TABLE 8-7. Sodium Adequate Intakes, Adults 19 Years of Age and Older.

TABLE 8-7

Sodium Adequate Intakes, Adults 19 Years of Age and Older.

Pregnancy

Starting early in pregnancy, there are considerable increases in plasma volume, interstitial space, and intercellular water (Hytten, 1985; Picciano, 2003). With these expansions, there are also decreases in plasma osmolality and plasma sodium concentrations (Cheung and Lafayette, 2013). Expansion of the extracellular fluid indicates an alteration in the homeostasis of the total body water. This change is accompanied by increased cardiac output, reduced systolic blood pressure, and increased vascular perfusion of organs and tissues, all of which result in increased kidney volume. Additionally, there are increases in renal blood flow, the glomerular filtration rate, and tubular reabsorption of sodium. There is increased renal clearance of low-molecular-weight solutes and creatinine clearance progressively increases throughout gestation (Cheung and Lafayette, 2013). These changes are highly influenced by progesterone. In addition to inducing smooth muscle relaxation and vasodilation, progesterone also reduces the response of the distal tubules to aldosterone, although aldosterone production also increases in early pregnancy (Soma-Pillay et al., 2016).

Circulating concentrations of all elements of the RAAS increase during pregnancy. In populations with extremely low salt intake (e.g., the Yanomamo tribe), pregnant women had higher plasma renin activity and serum aldosterone concentrations compared to nonpregnant women and no adverse gestational outcomes were reported (Oliver et al., 1981). The range of physiological adaptations during pregnancy is not fully understood, such as the production of hormones involved in the regulation of body water and a decreased responsiveness of receptors, such as the renin angiotensin system, to these hormones (Cheung and Lafayette, 2013). Additionally, the relationship between sodium intake and these volume changes is not clear, nor is the role of sodium in maintaining total body water volume during gestation fully understood (Brown and Gallery, 1994; Duvekot et al., 1993; Schrier and Briner, 1991).

Sodium accretion during pregnancy ranges from 2,100–2,300 mg (90–100 mmol) of additional sodium over the gestational period, estimated to amount to an additional 69 mg/d (3 mmol) (IOM, 2005). These cumulative gains in total body sodium provide for the products of conception (fetus, placenta, and amniotic fluid), and maintain the rise in plasma volume and interstitial space (Brown and Gallery, 1994).

The committee agrees with the 2005 DRI Report that there is a lack of evidence to suggest that sodium requirements of pregnant females differ from that of nonpregnant females. Accordingly, the sodium AI for pregnant females is determined to be 1,500 mg/d (65 mmol/d) (see Table 8-8).

TABLE 8-8. Sodium Adequate Intakes, Pregnant Females.

TABLE 8-8

Sodium Adequate Intakes, Pregnant Females.

Lactation

There is limited evidence regarding maternal sodium requirements during lactation. Sodium is excreted in breast milk (see the Infants 0–12 Month of Age section above), but the concentrations are determined by an electrical potential gradient, rather than by maternal dietary intake (IOM, 1991). To that end, the sodium requirements for lactating females does not appear to differ from that of nonpregnant, nonlactating females. Accordingly, the sodium AI for lactating females is determined to be 1,500 mg/d (65 mmol/d) (see Table 8-9).

TABLE 8-9. Sodium Adequate Intakes, Lactating Females.

TABLE 8-9

Sodium Adequate Intakes, Lactating Females.

SUMMARY OF UPDATED SODIUM ADEQUATE INTAKE VALUES

Aligned with the 2005 DRI Report, limitations in the evidence precluded this committee from establishing sodium EARs and RDAs. As such, the sodium AIs were updated. This committee's derivation of the sodium AI integrates consideration of a different collection of evidence than what was used in the 2005 DRI Report. Particularly, the committee not only considered evidence from the DASH-Sodium trial, but other trials that achieved low sodium intakes that did not report sodium deficiency among its participants. This committee also integrated into its consideration the best available balance study conducted among adults. The committee's review of potential harmful effects of low sodium intake revealed a heterogeneous body of evidence, which is insufficient to identify health risks associated with low sodium intakes. The sodium AIs have been revised for infants 0–6 months of age, children and adolescents 1–13 years of age, and adults 51 years of age and older.6 For infants 0–6 months of age, updated sodium AI stems from this committee's approach to estimating sodium concentrations in breast milk. For children and adolescents 1–18 years of age, the committee used sedentary EERs to extrapolate from the adult AI. This extrapolation approach differs from the approach used in the 2005 DRI Report, which used energy estimates from proxy- and self-reported 24-hour dietary recalls to extrapolate. Finally, the 2005 DRI Report used self-reported energy intake to extrapolate the sodium AI for adults 19–50 years of age to adults 51 years of age and older. This committee did not extrapolate for older adults owing to limited evidence, particularly with older adults. For context, a comparison of the sodium AIs established in this report and those that were established in the 2005 DRI Report are presented in Table 8-10.

TABLE 8-10. Comparison of Sodium Adequate Intakes Established in This Report to Sodium Adequate Intakes Established in the 2005 DRI Report.

TABLE 8-10

Comparison of Sodium Adequate Intakes Established in This Report to Sodium Adequate Intakes Established in the 2005 DRI Report.

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Footnotes

1

Chien et al. (2008) did not explicitly state how the overnight urine sample was used to estimate 24-hour urinary sodium excretion. A paper by Kawasaki et al. (1993) was cited in a general description of sample collection and is presumed to be the equation used.

2

From three to seven 24-hour urinary sodium measurements during the trial periods.

3

From three to seven estimated 24-hour urinary sodium excretions from sodium concentration of 24-hour urine using the Kawasaki formula.

4

From a 24-hour urinary sodium measured at the beginning of each trial.

5

A 24-hour urinary sodium estimated from sodium concentration of the first 24-hour urine using the Kawasaki formula.

6

This text was revised since the prepublication release.

Copyright 2019 by the National Academy of Sciences. All rights reserved.
Bookshelf ID: NBK545436

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